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Background and Purpose: The topotherapy technique was recently suggested as a robust alternative to helical radiation delivery for total body irradiation (TBI). It allows to deliver a discrete number of beams with fixed gantry. A Topotherapy-based low-dose TBI technique was optimized and clinically implemented. Materials and methods: TBI delivery was split in two parts: the first treating from the head to half thigh and the second the remaining legs. An in-silico investigation aimed to optimize plan parameters was first carried out on four patients. For the upper plan, field width and pitch were fixed to 5 cm and 0.5: the combined impact of five modulation factor (MF) values and different field configurations (6/8/12 fields) was investigated. For the lower plan, two anterior/posterior beams (field width: 5 cm; pitch: 0.5; MF:1.5) were used. After assessing the optimal technique, set-up/quality assurance/image-guidance procedures were defined and the technique clinically implemented: 23 patients were treated up to now. Results: The best compromise between treatment time and planning target volume (PTV) coverage/homogeneity was found for MF = 1.5 and 8 fields. All clinical plans were automatically optimized using an “ad-hoc” plan template: excellent PTV coverage (PTV95%>98.5%) and homogeneity (median SD:4%) were found with a median beam-on time of 17/9 min for the upper/lower plan. All patients were successfully treated and transplanted. Conclusions: TBI delivered with the topotherapy approach robustly guarantees adequate coverage and dose homogeneity. Semi-automatic clinical plans can be quickly generated and efficiently delivered. Keywords: TBI, TomoDirect, Tomotherapy, Automatic planning